My perspectives on IBD at DDW are based on overall developments from the past year, perhaps more so than what was presented and amplified at the conference presentations and DDW meetings with IBD and industry colleagues
In my mind, the best way to have an impact on Crohn’s disease in 2025 is to treat it with an advanced agent (biologic or small molecule) at the earliest time course for a patient with a poor prognosis (risk of progression to strictures/fistula/surgery). These features according to U.S. and European guidelines include patients with earlier onset IBD (excluding very early onset-IBD, which are primarily genetically driven), extensive disease, extra-intestinal complications, metabolic complications (anemia, low albumin), high inflammatory burden (e.g. high CRP), presenting with perianal disease, and deep ulcers. Although “refractory disease” and “need for steroids” are included in the category of moderate-to-severe disease, these are not required to categorize patients who will benefit from earlier effective therapy. Indeed, 80% of patients presenting with Crohn’s disease will meet criteria for poor prognosis, i.e., moderate-severe disease, which can be diagnosed at presentation. Same, by the way, for ulcerative colitis. In contrast, bio-naïve patients entering clinical trials for moderate-severe disease have average disease durations over eight years. Analyses from virtually all these trials demonstrate superior efficacy for patients with less than two years of disease, and the recently published PROFILE study enrolled patients into infliximab plus azathioprine therapy within weeks of the diagnosis, demonstrating that ~80% of patients were in sustained steroid-free and surgery-free remissions.
Combine these observations with increasing data demonstrating serologic and laboratory evidence preceding symptomatic disease and subsequent diagnoses by over six years. At diagnosis, Crohn’s disease is not a new onset but often has been brewing in the mucosa and through the bowel wall. This has led to an increase in the possibility of intercepting the disease earlier, which is more amenable to bowel repair and tissue healing.
Given that 40% of the risk factors for IBD are modifiable, the potential for early disease intercept blends with the potential for actual disease prevention. These modifiable factors include: vaginal vs C-section deliveries, breast vs bottle feeding, avoidance of antibiotics in early life, living with furry pets, healthy diets, avoiding ultra-processed foods and emulsifiers, and many other potential environmental exposures. At DDW 2025, one of the high-impact presentations pertained to the ADDAPT trial that randomized patients to diets with low or usual amounts of emulsifiers and demonstrated both reductions in symptoms and a reduction in fecal calprotectin in reduced-emulsifier diets.
Furthermore, the therapeutic ceiling in Crohn’s disease is more likely to benefit from earlier disease treatment than a combination of mechanisms of action (MOA).
The new agents likely to be approved for IBD are the TL1A antagonists that may or may not come with a companion diagnostic test that boosts the efficacy. The potential companion diagnostic would come with questions regarding how much of a boost would be expected, whether a positive biomarker would be required to prescribe the agent, and whether insurance requires the biomarker or limits patients to biomarker-positive patients. If third-party payers limit approval to biomarker-positive patients, will the drug be marketable with a limited population of patients with moderate-severe criteria?
From the standpoint of improving the therapeutic ceiling with combination therapies (which we have always used in IBD: steroids and immunomodulators, biologics with immunomodifiers, etc.), which combinations of mechanisms would be most rational and safe? And who will pay for any incremental benefit? In any event, numerous clinical trials are being performed in and outside the U.S. with combinations of biologics (e.g., TNFi + Il-23i, JAKs + vedolizumab, etc). This will likely be read out over the next few years. Meanwhile, to prescribe combination advanced therapies, clinicians need to stay under the radar with one biologic (medical plan) and another, or small molecule (pharmacy plan), or a GI prescribing one MOA and a dermatologist or rheumatologist prescribing the second agent. Further, should the combinations be concurrent or sequential, and can one induce, and the second, maintain, or even be used with a third agent, as was done in the EXPLORER trial?
Unfortunately, IBD 2025, as exemplified at DDW 2025, remains complicated.
Dr. Hanauer has no relevant conflicts of interest to report.
Illustration by April Brust
